Pathologists have long recognized that a significant percentage of the mass of a tumor consists of non- transformed cells infiltrating the malignancy. Nowhere has the fascination with these responding host elements been greater than with B cell lymphomas. Mechanistically, the infiltrating cells have been implicated as mediating tumor promotion and survival, or alternatively resisting tumor progression through immune surveillance. Recent progress in profiling gene expression in certain lymphoma subtypes has revealed strong correlations between host immune signatures and clinical prognosis, providing compelling evidence that cancer-extrinsic factors can have a profound impact on cancer biology. While high overall T cell frequencies found within some tumors portend a favorable outcome, the relative abundance of regulatory T cells (Tregs) correlates with short remissions and decreased survival. Although several cell types are capable of suppressing tumor-specific immunity, a subset of CD4+CD25+foxp3+ T cells appears to be among the most potent inhibitors of immune effector function. There are several features of Treg biology that are especially relevant to lymphoma pathogenesis. Lymphomas have been shown to be rich in cytokines such as IL10, IL13, and TGF2, which promote Treg induction or amplification of their suppressive function. Some of the cytokines elaborated by Tregs may serve as survival factors for transformed B cells. Finally, as lymphoma cells constitutively express MHC class II antigens, they are capable of activating CD4+ Tregs directly, blocking the local execution of effector function of a systemically generated (e.g. vaccine induced) T cell response. The central focus of this proposal is to fully characterize the interactions between Tregs, T effector cells, and B cell lymphoma using animal models, with the objective of identifying cellular and molecular targets for therapeutic manipulation. Specifically, we will: 1. Use a mouse model of B cell malignancy to define the influence of Tregs on disease progression, and the features of the tumor microenvironment that support the induction and/or amplification of Tregs. 2. Define the role of direct MHC II antigen presentation by lymphoma cells in mediating CD4+ Treg dependent inhibition of anti-lymphoma effector responses at the site of tumor. 3. Examine the impact of drugs and antibodies targeting Treg depletion, inhibitors of Treg function, and compounds seeking to block Treg reinduction/recruitment once depletion has been achieved. PUBLIC HEALTH RELEVANCE: Lymphomas are cancers of the cells of the immune system. Normal immune cells can become alerted to lymphoma and attempt to eliminate it. However one class of cells (so-called regulatory T cells) can inhibit this. Understanding how these cells work will enable strategies to bypass this suppression. Lymphomas are cancers of the cells of the immune system. Normal immune cells can become alerted to lymphoma and attempt to eliminate it. However one class of cells (so-called regulatory T cells) can inhibit this. Understanding how these cells work will enable strategies to bypass this suppression.